CRISPR screens decode cancer cell pathways that trigger γδ T cell detection

Murad R. Mamedov (), Shane Vedova, Jacob W. Freimer, Avinash Das Sahu, Amrita Ramesh, Maya M. Arce, Angelo D. Meringa, Mineto Ota, Peixin Amy Chen, Kristina Hanspers, Vinh Q. Nguyen, Kirsten A. Takeshima, Anne C. Rios, Jonathan K. Pritchard, Jürgen Kuball, Zsolt Sebestyen, Erin J. Adams and Alexander Marson ()
Additional contact information
Murad R. Mamedov: Gladstone-UCSF Institute of Genomic Immunology
Shane Vedova: Gladstone-UCSF Institute of Genomic Immunology
Jacob W. Freimer: Gladstone-UCSF Institute of Genomic Immunology
Avinash Das Sahu: Dana-Farber Cancer Institute
Amrita Ramesh: University of Chicago
Maya M. Arce: Gladstone-UCSF Institute of Genomic Immunology
Angelo D. Meringa: University Medical Center Utrecht
Mineto Ota: Gladstone-UCSF Institute of Genomic Immunology
Peixin Amy Chen: Gladstone-UCSF Institute of Genomic Immunology
Kristina Hanspers: Gladstone Institutes
Vinh Q. Nguyen: Gladstone-UCSF Institute of Genomic Immunology
Kirsten A. Takeshima: Gladstone-UCSF Institute of Genomic Immunology
Anne C. Rios: Princess Máxima Center for Pediatric Oncology
Jonathan K. Pritchard: Stanford University
Jürgen Kuball: University Medical Center Utrecht
Zsolt Sebestyen: University Medical Center Utrecht
Erin J. Adams: University of Chicago
Alexander Marson: Gladstone-UCSF Institute of Genomic Immunology

Nature, 2023, vol. 621, issue 7977, 188-195

Abstract: Abstract γδ T cells are potent anticancer effectors with the potential to target tumours broadly, independent of patient-specific neoantigens or human leukocyte antigen background1–5. γδ T cells can sense conserved cell stress signals prevalent in transformed cells2,3, although the mechanisms behind the targeting of stressed target cells remain poorly characterized. Vγ9Vδ2 T cells—the most abundant subset of human γδ T cells4—recognize a protein complex containing butyrophilin 2A1 (BTN2A1) and BTN3A1 (refs. 6–8), a widely expressed cell surface protein that is activated by phosphoantigens abundantly produced by tumour cells. Here we combined genome-wide CRISPR screens in target cancer cells to identify pathways that regulate γδ T cell killing and BTN3A cell surface expression. The screens showed previously unappreciated multilayered regulation of BTN3A abundance on the cell surface and triggering of γδ T cells through transcription, post-translational modifications and membrane trafficking. In addition, diverse genetic perturbations and inhibitors disrupting metabolic pathways in the cancer cells, particularly ATP-producing processes, were found to alter BTN3A levels. This induction of both BTN3A and BTN2A1 during metabolic crises is dependent on AMP-activated protein kinase (AMPK). Finally, small-molecule activation of AMPK in a cell line model and in patient-derived tumour organoids led to increased expression of the BTN2A1–BTN3A complex and increased Vγ9Vδ2 T cell receptor-mediated killing. This AMPK-dependent mechanism of metabolic stress-induced ligand upregulation deepens our understanding of γδ T cell stress surveillance and suggests new avenues available to enhance γδ T cell anticancer activity.

Date: 2023
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DOI: 10.1038/s41586-023-06482-x

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